A novel therapeutic approach via modulation of sphingolipid signaling in rosacea
Dr. Yoshikazu Uchida, research dermatologist, and Dr. Peter Elias, professor of dermatology at the University of California-San Francisco

Dr. Yoshikazu Uchida and Dr. Peter Elias have overcome a challenge that may lead to important advances in the treatment of rosacea.

In earlier studies, they found that stress to the skin cells caused by ultraviolet radiation, heat or other rosacea triggers results in a cascade of events in the body in which the production of one substance leads to another. These substances include the protective antimicrobial peptide called cathelicidin (CAMP) that speeds physical repair, but worsens rosacea symptoms. The next step was to discover how to reduce this peptide without limiting the body’s ability to defend and repair itself.

In order to preserve CAMP’s benefits, the researchers examined elements along the pathway to its production and found a substance known as SP1 (a type of lipid) that is responsible for the upstream signal that eventually leads to increased CAMP production.

Fortunately, they discovered there is another lipid metabolite, known as C1P, that stimulates production of other protective peptides, which in turn suppress the overproduction of CAMP, the substance that leads to rosacea symptoms. They noted that blocking or changing the metabolic pathway with a medication at this particular point could suppress inflammation and simultaneously stimulate the skin’s antimicrobial defense, potentially leading to the development of new types of therapy for rosacea.

The role of mast cells in rosacea inflammation
Dr. Anna Di Nardo, associate professor of medicine at the University of California-San Diego.

A team led by Dr. Anna DiNardo, associate professor of medicine of the University of California-San Diego, found that mast cells play a direct role in the activation of certain types of cathelicidins, an enzyme involved in the innate immune response that is over-produced in people with rosacea. Studying the process in mice, Dr. DiNardo's team determined that when exposed to a neuropeptide called PACAP, mast cells produce enzymes that trigger the production of cathelicidins. In mice bred to lack mast cells, this chain reaction did not occur.

In their next study, also supported by an NRS research grant, Dr. DiNardo's team will determine whether use of a mast cell stabilizer known as cromolyn sodium will decrease symptoms of rosacea. In addition, they will test to see if levels of the enzymes tryptase and chromotryptase -- typically higher in rosacea patients -- revert to normal after application of the mast cell stabilizer, and which of the enzymes is more important in the process.

Genetics have long been thought to play a role in rosacea, but researchers had yet to isolate their influence. In what may be the first study of rosacea to measure and define genetic and environmental contributions, Dr. Daniel Popkin, assistant professor of dermatology at Case Western Reserve University, and colleagues have found that genetics and environmental factors may contribute equally to the disorder.

To examine and isolate the potential genetic and environmental factors that may be involved in rosacea, the researchers studied a sample of 275 twin pairs (550 individuals) in whom at least one sibling has rosacea, recruited at the Twin Day Festival in Twinsburg, Ohio, near Cleveland. The study group included 233 pairs of identical twins and 42 pairs of nonidentical twins. Participants were scored based on the National Rosacea Society’s grading system and a physical examination by board-certified dermatologists. The researchers found that the disorder occurred significantly more often in both identical twins than in both members of a pair of fraternal (nonidentical) twins, and noted the association held true even after such common rosacea risk factors as age and skin type were accounted for, suggesting that genetics may play a substantial role in rosacea.

The researchers then evaluated factors such as gender, age, smoking/alcohol consumption history, heart health and lifetime sun exposure to determine the influence of certain environmental variables on the disease, and found that a higher rosacea score was positively associated with age and lifetime ultraviolet radiation exposure. They also found correlations with body mass index (BMI), smoking, alcohol consumption, cardiovascular issues and skin cancer. The researchers noted that although alcohol has been found to be a trigger of rosacea symptoms, it has not been identified as risk factor for development of the disorder. However, they did point out that the correlation between BMI (body mass index) and cardiovascular disease may be an opportunity for additional analysis. Recent studies have further highlighted a potential link between rosacea and the increased risk of cardiovascular disease.

Kallikrein protease inhibitors in the pathogenesis of rosacea
Dr. Ulf Meyer-Hoffert and Dr. Thomas Schwartz of the Department of Dermatology, University Clinic Schleswig-Holstein, Germany.

Kallikrein-related peptidases (KLKs), a family of proteases recently identified as having a possible role in the development of rosacea, may help provide a pathway to controlling rosacea’s signs and symptoms, according to an article by Drs. Jan Fischer and Ulf Meyer-Hoffert of the University Hospital Schleswig-Holstein in Germany in the journal Thrombosis and Haemostasis.

Proteases are enzymes that occur in all lifeforms, from single-celled organisms to plants and animals, for various metabolic processes. For example, acid proteases secreted into the stomach enable the digestion of protein in food, and other proteases present in blood play a role in clotting.

Kallikrein-related peptidases have many biochemical activities. Already recognized as biomarkers for cancer, certain types of KLKs in the surface of the body have been found to be involved in the normal shedding of the outermost layer of skin, the authors noted. Moreover, KLKs have been described as processing cathelicidins, protective antimicrobial peptides that can speed physical repair, but have been found to worsen rosacea symptoms.

The authors noted that interference in KLK activity may have therapeutic potential. For example, an antibiotic with anti-inflammatory properties was shown to inhibit KLKs and the subsequent activation of cathelicidin, which may be why it is effective in rosacea, they said.

They noted that further study of regulation of KLK activity may yield insights into therapeutic intervention.

Publication of results: Fischer J, Meyer-Hoffert U. Regulation of kallikrein-related peptidases in the skin – from physiology to diseases to therapeutic options. Thrombosis and Haemostasis 2013;110:442-449.

Functional role of PACAP and its receptors in neurovascular aspects of rosacea
Dr. Ferda Cevikbas, postdoctoral fellow, and Dr. Martin Steinhoff, professor of dermatology, University of California-San Francisco.

Researchers have found a potential connection between the nervous system and the redness and stinging of subtype 1 (erythematotelangiectatic) rosacea.

Drs. Ferda Cevikbas and Martin Steinhoff, University of California-San Francisco, noted that the flushed face of rosacea is often accompanied by stinging and burning, signs of nerve activation. They theorized this may signal a dysfunction in communication between the nerves and the vascular system.

A neuropeptide — a molecule linked to the nervous system — called pituitary adenylate cyclase-activating polypeptide (PACAP) was recently recognized as playing a role in regulating the blood vessels, they noted. However, while PACAP has been identified as affecting inflammation in various animal diseases, its role in human skin and skin disease is poorly understood.

Drs. Cevikbas and Steinhoff administered PACAP into skin on the underside of the forearms of volunteers, and found that the neuropeptide caused flushing, swelling and itching, though not pain. The investigators noted that PACAP may have a role in pain in combination with other factors, and suggested that blocking PACAP may be a potential treatment to relieve the redness and flushing of rosacea.

A malfunction in part of the body's nervous system may be linked to the redness as well as the bumps and pimples of rosacea, according to a recently completed study by Dr. Akihiko Ikoma and colleagues at the University of California-San Francisco.

The investigators took blood and biopsy samples from members of 10 families in which some individuals had rosacea. Through innovative biochemical and genetic testing, they found those with rosacea suffered from irregularities in a variety of transient receptor potential (TRP) ion channels, which serve as prominent components of the nervous system.

Because a variety of TRP channels can be activated by factors that trigger rosacea symptoms, the researchers noted, impaired functioning of these channels may play a critical role in the development of the disorder.

For example, TRPV1 is activated by capsaicin, a substance present in spicy food, as well as by heat or under inflammatory conditions. TRPV2 may play a role in innate immunity, inflammation and the sensing of heat. TRPV4 is also activated by moderate heat and may promote flushing, stinging and burning.

The researchers also found the immune system of those with subtype 1 (erythematotelangiectatic) rosacea, characterized by flushing and redness, showed significantly increased reactivity for TRPV2 and 3, as well as gene expression of TRPV1. Subtype 2 (papulopustular) rosacea, characterized by bumps and pimples, showed enhanced reactivity of the immune system for TRPV2 and 4, and had gene expression of TRPV2. These TRP nerve channels may therefore be promising targets in the development of future rosacea therapy, the researchers said.

New medical research into the process of facial flushing and redness has found that individuals with rosacea produce greater nerve, blood flow and sweating responses than people without the disorder when exposed to increased heat or stress. Results of the National Rosacea Society-funded study also uncovered a role for the sympathetic nervous system, which controls the “fight or flight” response and other key involuntary functions such as heart rate, digestion, breathing and perspiration.

To increase body temperature, the researchers had 10 rosacea patients and 10 healthy control individuals wear a tight-fitting suit lined with tubes carrying water heated to 115°F until their body temperature increased by approximately 2°F. Each person was then precisely measured for supraorbital nerve activity (a nerve just above the eyebrow that serves the forehead skin), forehead skin blood flow and forehead sweat rate.

The researchers found that rosacea patients had higher skin blood flow and sweating rates compared to normal subjects both before and after the heating began, and their skin blood flow and sweating also began to increase more rapidly during heating.

In a separate part of the study, heart rate, supraobital nerve activity and blood pressure were monitored in 12 rosacea patients and 12 healthy control subjects during mental and physical tasks. These included performing fast-paced mental subtraction exercises for two minutes, using hand gestures to indicate answers, and tightly squeezing a handgrip for two minutes.

While heart rate and blood pressure were the same between the groups during the hand exercises, skin blood flow was higher duringmental arithmetic in the rosacea patients. The rosacea patients also experienced heightened sympathetic nerve activity compared to those without rosacea during both the mental and physical portions of the test. The greater responses in rosacea patients occurred in the sympathetic nervous system, a part of the body’s autonomic nervous system that controls involuntary functions such asheart rate, digestion, breathing and perspiration. This portion of the autonomic nervous system functions largely below the level of consciousness and has been shown to respond to emotion.

Clinical and molecular analysis of differences between rosacea and photoaging
Dr. Yolanda Helfrich, assistant professor of dermatology at the University of Michigan.

In a study of 27 patients with subtype 1 rosacea, 18 with subtype 2 rosacea, 19 with photodamaged skin and prominent telangiectasia and 11 control subjects without rosacea or sun damage, Dr. Yolanda Helfrich, assistant professor at the University of Michigan, found that patients with subtype 1 rosacea had a greater number of mast cells that were discharging their contents than the control subjects.

Mast cells are found in skin tissue surrounding blood vessels and nerves, and release many mediators involved in rosacea, including histamine, associated with flushing. Since virtually all the mast cells in the rosacea patients were positive for interleukin 17, Dr. Helfrich noted that this cytokine — which plays a key role in development of rheumatoid arthritis and psoriasis — may also contribute to rosacea.

In addition, though some individuals with skin aging due to sun exposure also had prominent facial telangiectasia, she found significant biological differences between this group and those with rosacea, suggesting that the presence of visible blood vessels alone should not necessarily lead to a diagnosis of rosacea.

Role of beta-arrestin in cutaneous flushing
Dr. Robert W. Walters, assistant professor, Division of Dermatology, and Dr. Robert J. Lefkowitz, professor, Department of Medicine, Duke University Medical Center.

Researchers have now identified the molecular pathway for flushing caused by niacin — also known as vitamin B3 or nicotinic acid, and found in many foods — according to a study recently completed by Dr. Robert Walters and colleagues at Duke University and funded by the National Rosacea Society. The new findings may lead to future improvements in the treatment or prevention of rosacea, which is commonly associated with flushing.

"So little is known about the flushing responses in rosacea, and the first step toward their control is to understand the nature of their causes," Dr. Walters said. "Since niacin is often a trigger factor for flushing, it was important to investigate this response at the molecular level."

He noted that this substance is an essential vitamin found in an extensive range of foods, including foods reported to trigger rosacea flare-ups in some individuals, such as beef liver, yeast, avocadoes and spinach. While niacin deficiency leads to pellagra — a disease associated with skin problems, weakness and dementia — he noted that it has also been associated with severe flushing in individuals taking large amounts as a supplement.

The researchers studied this process in microscopic cultures of cells and found that when one of the body's niacin receptors — cell surface protein GPR109A — is stimulated, both G-proteins and beta-arrestin proteins are activated. A receptor is a cellular structure that accepts the molecular structure of a specific chemical agent, and then acts on nervous tissue to produce a physiological response.

In the new study, the investigators found that niacin-like drugs stimulating only G-proteins do not induce flushing, suggesting that it is instead the beta-arrestins that cause the flushing. The beta-arrestins were further implicated when it was observed that they are required for activation of the enzyme cPLA2, which produces molecules that act directly on blood vessels in the skin to increase blood flow. As final proof, beta-arrestin activated by niacin was demonstrated to be a requirement for the flushing to occur.

"By defining the molecular pathway for flushing that begins with niacin, new therapies might be developed to block this process," Dr. Walters said. He noted that other causes of flushing may utilize the same pathway, suggesting it could also be an important mechanism for flushing in general.

A study funded by the National Rosacea Society provides further evidence that rosacea may be far more common than widely believed, and also assesses the potential significance of sun exposure.

The study, presented at the 2008 British Association of Dermatologists meeting by Dr. Maeve McAleer and colleagues at Mater Misericordiae University Hospital and the School of Public Health and Population Science, University College, Dublin, found that 14.4 percent of 1,000 subjects examined in Ireland had rosacea.

This high prevalence rate is comparable to preliminary study results that found rosacea in 16 percent of Caucasian women in the United States. The U.S. data, reported by Dr. Alexa Boer Kimball, director of the clinical unit for research in skin care at Harvard Medical School, were based on examination of high-resolution digital photographs of 2,933 volunteers. Another study of 806 office workers examined in Sweden found a rosacea prevalence of 14 percent in women and 6 percent in men.

While the more recent studies are based on the standard classification system published by the National Rosacea Society Expert Committee for the Classification and Staging of Rosacea in 2002, Dr. McAleer noted that earlier studies did not have defined criteria for diagnosing the condition. To investigate the potential effects of sun exposure, the Irish study included 500 residents of the Aran Islands, an area off the western coast of Ireland, and 500 hospital workers in Dublin. The Aran Islanders reportedly had greater sun exposure, due to their outdoor occupations of fishing and farming, compared with the hospital workers.

The researchers found that the Aran Islanders and the hospital workers had similar rates of subtype 2 (papulopustular) rosacea, characterized by bumps and pimples, at 2.8 percent and 2.6 percent, respectively. However, they found that 16.3 percent of the Aran Island group had subtype 1 (erythematotelangiectatic) rosacea, characterized by facial redness, compared with a subtype 1 prevalence rate of 6.8 percent in the hospital workers (a statistically significant difference).

Role of proteases and endothelin-converting enzyme in rosacea
Dr. Martin Steinhoff, department of dermatology, University of Muenster, Germany.

Dr. Martin Steinhoff and Dr. Thomas Luger, Department of Dermatology, University of Muenster, have been studying biological receptors, structures in human cells that bind with particular substances in the body to cause certain reactions or responses. Receptor dysfunctions may lead to disease, including rosacea, and thus identification of the mechanisms of these processes often leads to important therapeutic advances.

For example, proteinase-activated receptor 2 (PAR 2) can serve as a receptor for several molecules, including dust mite antigens and bacterial proteases, which have a high impact on inflammatory response in the skin. In a National Rosacea Society-funded study, the researchers are now defining which of the type of proteases known as kallikreins may be involved in the inflammatory responses as well as the stinging, burning and itching of rosacea. As part of their multi-pronged investigation, they recently discovered that endothelin-converting enzyme (ECE) acts on the neuropeptides known as substance P and calcitonin gene-related peptide (CGRP), and noted that any substance that inhibits ECE may be effective in the treatment of rosacea.

New clues to help unlock the mystery of rosacea were identified in a National Roscacea Society-funded study in which researchers used advanced technology to evaluate the skin of patients successfully treated with pulsed dye lasers (PDL) or intense pulsed light (IPL).

"We are pleased to see interesting findings in this small pilot study that not only help reveal the underlying disease process, but may also provide a basis for developing more targeted therapy in the future," said Dr. Nancy Samolitis, visiting instructor in dermatology at the University of Utah and investigator in the study.

Before treatment the researchers found elevated levels of vascular endothelial growth factor (VEGF), associated with the development of visible blood vessels (telangiectasia), in five of the 10 rosacea patients. In four of these subjects — three in the PDL group and one in the IPL group — the level decreased after therapy.

Eight of the patients were also found to have elevated cathelicidins, natural antimicrobial agents linked in previous research to rosacea inflammation, and the level was reduced in three IPL- and two PDL-treated patients after treatment.

"The results of this study suggest that PDL and IPL may have a role in the reduction of telangiectasia," Dr. Samolitis said. "Our findings particularly suggest that cathelicidins and VEGF may play a role in the pathogenesis of rosacea and warrant further study."

Both the physicians and patients rated significant improvement in rosacea severity in the 10 individuals treated.

Although light sources are commonly used to remove visible blood vessels, their usefulness in reducing the redness of rosacea requires further study. Drug therapy is usually prescribed to control the bumps and pimples of rosacea and has been shown to significantly reduce the incidence of flare-ups.

Although they are normal inhabitants of human skin and cannot be seen, microscopic mites known as Demodex folliculorum may actually be something to blush about, as a new study funded by the National Rosacea Society (NRS) demonstrated for the first time that these invisible organisms may be a cause or exacerbating factor in rosacea.

"While it is well established that Demodex occur in far greater numbers on the faces of people with rosacea, it was uncertain whether they play a role in the development of the disorder," said Dr. Frank Powell, consultant dermatologist at Mater Misericordiae Hospital in Dublin, Ireland, who conducted the study along with colleagues at the National University of Ireland-Maynooth. "In other words, which came first, the mites or the rosacea? And now there is evidence that it might be the mites."

In the new study, published in the British Journal of Dermatology, the researchers identified Bacillus oleronius as distinct bacteria associated with Demodex mites. When analyzing blood samples using a peripheral blood mononuclear cell proliferation assay, they discovered that B. oleronius stimulated an immune system response in 79 percent of 22 patients with subtype 2 (papulopustular) rosacea, compared with only 29 percent of 17 subjects without the disorder.

"The immune response results in inflammation, as evident in the papules (bumps) and pustules (pimples) of subtype 2 rosacea," Dr. Powell said. "This suggests that these bacteria found in the mites could be responsible for the inflammation associated with the condition."

Dr. Powell noted that the potential role for the bacteria in subtype 2 rosacea is also supported by the fact that effective treatment includes antibiotics that destroy B. oleronius. Interestingly, he said, antibiotics that are not harmful to these bacteria generally are not effective in the management of rosacea.

"Although the mechanism of antibiotics in treating rosacea is not definitively understood, it has long been suggested that they work through anti-inflammatory action," he said. "However, other anti-inflammatory drugs are ineffective in treating rosacea, and immunosuppressive agents such as steroids can ultimately make the inflammation worse."

The researchers concluded that their study shows consideration must also be given to the potential for antibiotics to affect microorganisms such as B. oleronius or other follicular or mite-related bacteria.

Researchers have found that one of the most common and hard-working substances in the body may have a Jekyll and Hyde quality in rosacea patients, assuming a darker role when activated by flare-up triggers.

"Sometimes too much of a good thing turns out to be bad," noted Dr. Richard Granstein, chairman of dermatology at Cornell University, lead investigator in the ongoing research funded by the National Rosacea Society (NRS). "The key to improving therapy is to identify those inflammatory pathways involved with rosacea so they can be better controlled."

The researchers have discovered that when adenosine 5'-triphosphate (ATP) — a neurotransmitter and carrier of chemical energy throughout the body — is released into the skin by the nerves, a cascade of microscopic events may occur in rosacea patients that ultimately leads to the bumps and pimples of subtype 2 (papulopustular) rosacea.

"As with many disorders, inflammation represents a normal body process gone awry," Dr, Granstein explained. Inflammation is a protective response to injury or destruction of tissues that serves to destroy, dilute or wall off both the agent of injury and the injured tissue, so that tissue can repair itself.

The most evident outward signs and symptoms of inflammation are pain, heat, redness, swelling and loss of function. However, the biochemical processes that accomplish this reaction are complex, and involve dilation of blood vessels accompanied by increased blood flow, release of fluids and the movement of leukocytes — blood cells that engulf and digest bacteria and fungi and are an important part of the body's defense system, according to Dr. Granstein.

While ATP has many functions in the body, its role in the development of rosacea may involve its job as a messenger from the nerves. The nervous system regulates blood flow to the skin, using ATP to prompt the dilation of blood vessels following exposure to rosacea triggers such as sunlight, emotional stress or alcohol. This process may result in the flushing and redness of subtype 1 (erythematotelangectatic) rosacea.

According to Dr. Granstein, ATP has also been shown to be involved in the movement and buildup of leukocytes onto endothelial cells — cells that line the blood vessels. In rosacea, the researchers found that endothelial cells respond to ATP with changes in the expression of inflammatory cytokines and other substances that act to recruit inflammatory cells and may lead to rosacea's bumps and pimples.

"As we continue to learn more about the biochemical processes that lead to rosacea, we should increasingly be able to identify how signs and symptoms occur in order to develop appropriate means to prevent them," Dr. Granstein said. He noted that, while current therapies may block some of these pathways, the process is still unclear and should become increasingly evident through continuing research.

In previous NRS-funded studies, Dr. Granstein's team demonstrated that ultraviolet B (UVB) radiation, which is found in sunlight and causes sunburn, may increase vascular endothelial growth factor (VEGF), a regulator of blood vessel growth that may cause visible blood vessels (telangiectasia) associated with subtype 1 rosacea. In addition, they found that UVB may increase interleukin 8, which plays a role in inflammation.

Allergy-like reaction may trigger inflammation in rosacea
Dr. Richard L. Gallo, associate professor of dermatology and pediatrics at the University of California - San Diego, and Dr. Kenshi Yamasaki, Veterans Medical Research Center

The bumps (papules) and pimples (pustules) of rosacea, a widespread facial disorder affecting an estimated 14 million Americans, may be the result of an allergy-like reaction to environmental and emotional triggers, according to new study results presented at the National Rosacea Society (NRS) research workshop during the annual meeting of the Society for Investigative Dermatology in Philadelphia. The seventh annual NRS workshop was attended by more than 130 medical scientists from around the world.

"We are very excited about these findings because they may provide the basis for improving the treatment and management of this condition," said Dr. Richard Gallo, chief of the division of dermatology at the University of California-San Diego and lead investigator of the NRS-funded study. "By defining the process leading to the inflammation, new medications might be developed to block these effects."

Dr. Gallo explained that when the normal immune system is faced with any of a broad range of potential dangers — such as sun exposure, emotional stress, heat and spicy foods, among many others — receptors recognize potential danger and protect the body by prompting the production of protective substances that isolate and neutralize any harmful effects. With rosacea, however, these protective substances, like overzealous guards, turn the body on itself, leading to inflammation.

Using advanced mass spectrometry technology to analyze the biochemical composition of proteins in rosacea patients, the researchers discovered an abnormality in the production of protective molecules known as cathelicidins, Dr. Gallo said. In normal patients, the cathelicidins are found in a form that is inactive and would not lead to bumps and pimples. In rosacea patients, the forms of cathelicidins are different and lead to skin inflammation. The cause of this abnormality in cathelicidins seems to be due to an equally important problem in rosacea — an overabundance of yet another substance, called kallikrein, which can spur dormant cathelicidins into action.

"It appears that the combination of these two substances at abnormally high levels is a double whammy for rosacea patients," Dr. Gallo noted.

The researchers recently completed the picture when they were able to demonstrate that this process is linked to the actual formation of rosacea signs and symptoms. The skin of mice injected with the cathelicidins found in rosacea patients showed a dramatic inflammatory response — including bumps and pimples — while mice injected with normal cathelicidins showed no inflammation, either visually or under a microscope.

"The next step is to test these findings in human subjects through various therapeutic interventions," Dr. Gallo said. "As we gain a thorough understanding in humans, we can look for new medications that block this process in order to treat or prevent the inflammation associated with rosacea."

Role of serine proteinases and proteinase-activated receptors (PAR-2 and PAR-4) in the pathophysiology of rosacea.
Dr. Martin Steinhoff and Dr. Thomas Luger, Department of Dermatology, University of Muenster.

New research funded by the National Rosacea Society has found that certain molecular receptors and their activators may play a significant role in producing the redness, visible blood vessels and inflammation of rosacea.

A receptor is a structure in human cells that binds with particular activating substances in the body to trigger certain reactions or responses. Dysfunction of receptors often leads to disease. Accordingly, identification of the mechanisms of these processes, which may then be adjusted, often leads to important therapeutic advances.

Dr. Steinhoff and Dr. Luger examined how proteinase-activated receptor 2 (PAR-2) and its agonists may affect endothelial cell function in rosacea skin. PAR-2 can serve as a receptor for several molecules, including dust mite antigens and bacterial proteases, which have a high impact on inflammatory response in the skin.

The researchers found that PAR-2 agonists induce upregulation of several molecules related to microvascular endothelial cells, and that they regulate proliferation and differentiation in keratinocytes and induce the release of cytokines.

Additionally, PAR-2 agonists were found to cause erythema and vasodilation in human skin in in vivo studies, indicating a functional role for PAR-2 in human cutaneous blood vessel formation. Dr. Steinhoff and Dr. Luger also demonstrated that PAR-2 plays an important role in leukocyte adhesion to endothelial cells in the skin of mice. Moreover, in studying the effects of PAR-2 agonists on keratinocyte function, it was found that PAR-2 activates NFkB in humans, indicating a potential important role of this receptor in skin inflammation.

The researchers are now conducting further studies to determine whether PAR-2 or its agonists affect the expression of VEGF, known to trigger the formation of visible blood vessels, or nitrous oxide, which may hypothetically play a role in rosacea.

In a study funded by a grant from the National Rosacea Society (NRS), researchers may have uncovered clues that may lead to a diagnostic marker for subtype 4 (ocular) rosacea, a chronic condition that may have severe consequences if left untreated — including reduced vision. In publishing the final study results in the medical Journal of Proteome Research,1 the researchers noted that ocular rosacea often may be difficult to diagnose, especially in the absence of signs of rosacea on the skin. In addition, it may be frequently overlooked by non-eye doctors.

"Ocular rosacea is potentially a vision-threatening condition that may be easily missed," said Dr. Mark Mannis, chairman of ophthalmology at the University of California, Davis and one of the study's investigators. "We are excited that our study may ultimately lead to the first diagnostic test that could alert physicians to eye involvement before it grows more serious."

Samples of tears from 16 ocular rosacea patients and 21 individuals without rosacea were collected by Dr. Mannis and colleagues and were analyzed for the presence of oligosaccharides, a type of carbohydrate that may be found in the mucus component of the tear fluid. Oligosaccharides are known to be sensitive to the biochemical environment and could be an indicator of disease states.

The researchers found that the presence of high levels of oligosaccharides may be a diagnostic indication of ocular rosacea and that high levels of 13 particular types of the compound were associated with rosacea and may serve as more specific markers for the disorder. Since a general increase of oligosaccharides may not necessarily be specific to rosacea, they emphasized that the types of oligosaccharides found in greatest abundance in rosacea patients should be evaluated in further research for their specificity as markers for ocular rosacea.

Ocular rosacea may be present in varying degrees in up to 50 percent of rosacea sufferers. In an NRS survey of 1,780 rosacea patients reporting ocular symptoms, only 27 percent said they had been diagnosed with the condition, possibly indicating underdiagnosis. Typical symptoms of ocular rosacea may include a watery or bloodshot appearance, foreign body sensation, burning or stinging, itching, light sensitivity, blurred vision, and visible blood vessels or redness of the eyelid. A history of styes and feeling of dryness in the eyes are also key indicators.

"We plan to further investigate which types of oligosaccharides are the best indicators of rosacea in order to achieve even greater accuracy in distinguishing ocular rosacea from normal patients," Dr. Mannis said.

Effects of neuropeptides and sebocyte-derived factors on human dermal microvascular endothelial cells in the skin: A possible mechanism for the development of vascular and inflammatory lesions in rosacea.
Dr. Richard Granstein, Cornell University Medical School.

Results from previous research funded by the National Rosacea Society have led investigators Dr. Richard Granstein and colleagues at the Cornell University Medical School to focus in their current study on adenosine triphosphate (ATP), a natural substance in the body that may play a key role in the flushing, telangiectasia and bumps and pimples of rosacea.

In their earlier NRS-funded research investigating the biochemical pathways that regulate the growth of new blood vessels, flushing and inflammation, Dr. Granstein's group demonstrated that ultraviolet B (UVB) radiation, found in sunlight, may increase vascular endothelial growth factor (VEGF), a regulator of blood vessel growth, and may also increase interleukin 8, which plays a role in inflammation.

In addition, the researchers' early data indicated that endothelial cells — cells that line the blood vessels — respond to ATP with changes in the expression of inflammatory cytokines, which are proteins that act to recruit inflammatory cells. ATP also may affect vascular tone by inducing vasodilation — enlargment of the blood vessels — which may result in the appearance of redness.

Known as the "molecular currency" of intracellular energy transfer, ATP acts like a rechargeable battery and is able to store and transport chemical energy within cells. The substance not only is present in neurons, or nerve cells, which are affected by rosacea triggers such as stress, but is also essential to many cellular functions, according to Dr. Granstein.

"Its widespread presence suggests there may be many pathways by which ATP may mediate rosacea," Dr. Granstein said. "ATP may play a significant role in response to inflammation, and have a profound effect in response to rosacea triggers. If so, blocking these pathways may lead to major advances in therapy."

The researchers plan to look at this substance under a variety of different conditions and in different concentrations to track its potential role in rosacea.

Experimental studies in the pathogenesis of rosacea.
Dr. YaXian Zhen, scientific researcher, and Dr. Albert Kligman, professor of dermatology, University of Pennsylvania.

Dr. Zhen and Dr. Kligman explored similarities between acne vulgaris and rosacea. The researchers noted that in studies of more than 100 women with rosacea, about 40 percent reported having adolescent acne. Moreover, about 30 percent to 40 percent of the women who experienced acne during adolescence exhibited moderate flushing responses to common rosacea triggers.

In a further investigation of 15 female rosacea patients and five women without rosacea as controls, the researchers found that the rosacea patients had more characteristics common to acne than the control subjects. Facial oil production was about 40 percent greater; microcomedones, precursor to visible comedones (blackheads), were twice as numerous and larger in the rosacea patients than in the controls; and the density of the acne bacterium, Propionibacterium acnes, was nearly twice that of controls.

A bioengineering evaluation of facial rosacea.
Dr. Diane Thiboutot, professor of dermatology; Hilma Benjamin and Dr. Klaus Helm, Division of Dermatology, Pennsylvania State University College of Medicine.

In a study of the moisture level, elasticity, skin thickness, extent of photodamage and other characteristics of rosacea skin, investigators found rosacea patients had thicker facial skin than normal subjects, which might be a result of edema (swelling). However, the researchers found no significant difference in skin water loss and elasticity between the 20 rosacea patients and 20 patients without rosacea.

Their questionnaire revealed that rosacea patients, who are often affected by sun exposure, were more likely to keep the upper body covered from the sun while doing outdoor work and were less likely to have had sunburns that required medical attention. Despite their apparently reduced sun exposure, however, those with rosacea had more visible blood vessels and blood vessels with a larger diameter.

Vascular endothelial growth factor (VEGF), a regulator of blood vessel growth that may be associated with sun exposure, was highly expressed in the sebaceous glands of the rosacea patients, Dr. Thiboutot said. She noted that previous research has found VEGF may be involved in the formation of visible blood vessels in rosacea, and that rosacea patients may therefore be especially sensitive to sunlight.

In a small pilot study funded by a grant from the National Rosacea Society, 27 rosacea patients and a control group of 17 people without rosacea completed a survey about rosacea and the Tennessee Self-Concept Scale (TSCS), once at the beginning of the study and again after three months. No statistically significant differences in self-concept or role performance were shown between the gross scores of the rosacea group and the control group.

"There does, however, appear to be a logical pattern to the test scores, based on severity of condition," Lindow said. "For example, an interesting trend is seen of decreasing [self-image] scores corresponding with an increasing severity of illness."

The investigators believed the small sample size may explain the lack of statistically significant findings. Changes in self-concept would be expected to be subtle, correlating with the relative severity of the disorder, and therefore would be more easily detected in a larger sample size. They recommended a larger study be undertaken to examine this issue.

The role of bacterial antigen(s) in the etiology and persistence of papulopustular bacteria.
Dr. Kevin Kavanagh, Department of Biology, National University of Ireland - Maynooth, and Dr. Frank Powell, consultant dermatologist, Mater Misericordiae Hospital, Dublin.

Bacteria associated with microscopic mites known as Demodex folliculorum may play a role in the development of papulopustular (subtype 2) rosacea, according to the results of a study funded by a National Rosacea Society grant and reported at the 2004 annual meeting of the Society for Investigative Dermatology.

In the completed study, Dr. Kevin Kavanagh and colleagues found that the bacterium Bacillus oleronius stimulated an immune system response, inducing high levels of T-cell proliferation, in 79 percent of patients with subtype 2 rosacea, compared with only 29 percent of patients without the disorder. T-cell proliferation induces an inflammatory response, evident as papules and pustules.

"This indicates that the Bacillus bacteria found in the Demodex mite produce an antigen that could be responsible for the tissue inflammation associated with papulopustular rosacea," Dr. Kavanagh said.

The researchers located the bacteria in Demodex folliculorum, which are normal inhabitants of human skin. Because these microorganisms often occur in much greater numbers in patients with rosacea, researchers have long theorized that they may play a part in the development of the disorder.

The researchers offered several possibilities that may explain how Demodex and bacteria interact to cause inflammation in rosacea. The Demodex mites may carry the pathogenic bacteria into areas of the face susceptible to the changes of rosacea, so that the increased mite density in rosacea patients may result in a higher density of bacteria that produce the papules and pustules. Alternatively, Demodex mites may be attracted to an area of facial skin rich in these bacteria and increase in numbers in this "fertile territory."

Another possibility is that the mites in rosacea patients are infected with these bacteria, which in turn produce stimulatory antigens that trigger the disorder in susceptible patients.

Dr. Kavanagh noted that the potential role for bacteria in causing papulopustular rosacea is supported by the fact that typical treatment for rosacea initially includes oral antibiotics that destroy B. oleronius. Interestingly, he said, antibiotics that are not harmful to these bacteria generally are not effective in the management of rosacea.

Moreover, the possibility that antigens may play a role in disease processes has been demonstrated in other disorders. For example, antigens produced by Streptococcus and Staphylococcus bacteria have been linked with such disorders as psoriasis, food poisoning and toxic shock syndrome.

Dr. Kavanagh and his colleagues are now developing antibodies against the antigen produced by B. oleronius to confirm its presence on the faces of patients with papulopustular rosacea and to define its relationship with Demodex mites.

Immune system may trigger onset of rosacea symptoms
Dr. Richard Gallo, associate professor of dermatology and pediatrics at the University of California - San Diego and Dr. Masamoto Murakami, postdoctoral scientist, Veterans Medical Research Center.

Whether certain proteins made by the immune system may trigger the onset of rosacea is the subject of continuing research sponsored by National Rosacea Society research grants. While acting to protect the body, the proteins also may trigger some of rosacea's symptoms, the researchers hypothesize.

"If this theory proves true — that rosacea is in some way a disorder of the innate immune system — then completely new therapeutic approaches can be developed to treat this disease," Dr. Gallo said.

The immune system, which is responsible for the body's ability to combat illness and infection, produces its own antibacterial agents that fight disease and heal wounds, Dr. Gallo said. These natural substances act by eliminating the presence of harmful bacteria and activating other parts of a complex immune reaction. Either irritation or infection may stimulate the production of these proteins, he noted.

Dr. Gallo's laboratory is investigating whether the immune system response, including the expression of a natural protein called a cathelicidin, may cause some of the signs and symptoms of rosacea.

In their initial study, Dr. Gallo and his colleagues found an abnormally high level of cathelicidins upon histopathological staining in the skin of patients with rosacea. They further noted that some hallmarks of rosacea, including inflammation and growth of blood vessels, are associated with cathelicidins.

In a second study, the researchers are now investigating whether the redness, inflammation and blood vessel growth of rosacea are a result of an abnormal expression of this natural antibiotic. Using immunohistochemistry and quantitative polymerase chain reactions, Dr. Gallo and his colleagues found that in rosacea the chronic production of cathelicidins appears to be ineffective in inhibiting the spread of bacteria, and may instead simply trigger rosacea's signs and symptoms.

The researchers plan to further test their hypothesis by examining the effect of cathelicidins in mice and on human blood cells.

In research funded by the National Rosacea Society, Dr. Lerner examined the potential contribution of nitric oxide to the redness and inflammation of rosacea. Nitric oxide is a gas produced naturally in nearly all of the body's cells and is used by the nervous, immune and cardiovascular systems. Because nitric oxide is known to make blood vessels dilate, it was hypothesized that it may play a role in rosacea.

The study aimed to test for the presence of nitric oxide synthase (NOS), a nitric oxide-producing enzyme, and the gene that creates NOS in the skin of rosacea patients through in situ hybridization and immunoperoxidase.

The in situ hybridization test was inconclusive; the researchers had difficulty obtaining clean results from the probes, and high background levels made it difficult to isolate NOS readings.

In the immunoperoxidase test, stains of biopsies taken from the skin of rosacea patients showed a normal amount of NOS. This could be interpreted as indicating that nitric oxide is not a significant factor in rosacea. However, Dr. Lerner believes that different types and severities of rosacea should be tested before the molecule can be completely ruled out.

The researchers also determined how much of a known nitric oxide inhibitor is absorbed through the skin, so that the effects of suppressing nitric oxide might be tested.

In other research, Dr. Lerner is developing a mouse model of what happens in human skin when too much nitric oxide is present. He is attempting to produce transgenic mice in which the gene for NOS is expressed in the skin under the control of a promoter, so that application of a topical compound will cause production of nitric oxide. Among the potential outcomes to be observed is whether too much nitric oxide produces any signs of rosacea.

The greater warmth of the facial skin of rosacea sufferers may play a role in triggering the unsightly bumps and pimples that are common signs of this disorder, according to a new study funded by a grant from the National Rosacea Society and reported at the 2001 annual meeting of the Society for Investigative Dermatology.

In the completed study, Drs. Dahl and Schlievert found that at higher temperatures bacteria from the facial skin of both rosacea patients and people without rosacea released substantially more potentially toxic substances. The study noted that the surface temperature of facial skin in rosacea patients may be warmer than normal skin due to redness and flushing, and the resulting increase in toxic substances may lead to the bumps and pimples often associated with the disorder.

"Researchers have long wondered whether bacteria may be responsible for the inflammation, papules and pustules of rosacea, especially because these signs can be successfully treated with oral and topical antibiotics that destroy bacteria as well as reduce inflammation," Dr. Dahl said.

The researchers cultured samples of Staphylococcus bacteria from the pustules (pimples) of four untreated rosacea patients and the skin surface of four people without rosacea at both 86 and 99 degrees Fahrenheit. They found that, while the bacteria grew at the same rate in both the lower and higher temperatures, at the higher temperature the samples produced larger amounts of potentially toxic proteins.

In addition, some substances were secreted by the bacteria at the higher temperature that were not produced at the lower one. This included a type of enzyme known as a lipase — a protein that acts to speed chemical reactions — that may break down oils on the skin surface, potentially leading to blemishes and inflammation. Moreover, while all samples from rosacea patients produced the lipase, half of the samples from people without rosacea did not.

Dr. Dahl described several possible interpretations of these study results. Common bacteria may have a tendency to generate more of these irritating substances at the higher temperatures encountered on the faces of people with rosacea. Also, they may generate different harmful materials at these higher temperatures. The nature of these materials or the amounts produced could trigger papules and pustules.

Dr. Dahl further noted that other bacteria might also behave differently on the warmer skin of rosacea patients.

"Our findings suggest that temperature may change the toxicity of many types of common bacteria, opening a whole new avenue of research into this widespread but poorly understood disorder," Dr. Dahl said.

Sunlight and heat do not appear to cause visible blood vessels (telangiectasia) in rosacea patients by decreasing endoglin production, according to a study funded by a grant from the National Rosacea Society aimed at finding a cause for this common sign of rosacea.

Endoglin is a protein in human skin cells that plays a role in vascular development. In the completed study, Dr. Swerlick and other researchers had hypothesized that changes in endoglin expression in skin cells may cause telangiectasia in rosacea patients in a manner similar to that seen in a disorder known as hereditary hemorrhagic telangiectasia. They tested whether exposure to such environmental factors as sunlight and heat, which are often reported as rosacea triggers, may depress endoglin expression to allow the formation of visible blood vessels in rosacea patients. No effect was found from heat or sunlight on the expression of endoglin after blinded comparisons of skin samples stained for immunofluorescent identification of activity. The results of the study therefore suggest that no such relationships exist in rosacea.

The role of vascular endothelial growth factor in rosacea
Dr. Mina Yaar, professor of Dermatology, Boston University School of Medicine.

Sun exposure appears to trigger a substance in the body that may lead to the visible blood vessels that often appear with rosacea, a conspicuous facial disorder now estimated to affect 14 million Americans, according to research funded by the National Rosacea Society and reported at the 2002 annual meeting of the Society for Investigative Dermatology.

"Our initial study showed that sunlight may indeed have a role in causing rosacea," said Dr. Marita Kosmadaki, research fellow, Department of Dermatology, Boston University, who presented results of her research with Dr. Mina Yaar, professor of dermatology at Boston University.

Drs. Yaar and Kosmadaki found that exposure to ultraviolet (UV) radiation — a component of sunlight — led to the production of vascular endothelial growth factor (VEGF), a substance that has been linked to the development of visible blood vessels (telangiectasia).

"The melanin in the skin of darker-skinned individuals appears to make it difficult for UV radiation to reach the lower layers of the skin," Dr. Kosmadaki noted. "As a result, in darker-skinned individuals VEGF would tend to be induced only in the upper skin layers, and hence would not affect the blood vessels. In contrast, sufficient ultraviolet rays could induce VEGF synthesis in the deeper skin layers in fair-skinned individuals."

Because other researchers had found the production of VEGF can be triggered by another molecule called tumor necrosis factor (TNF), Drs. Yaar and Kosmadaki hypothesized that the UV radiation first induced the production of TNF, and its release in turn led to the synthesis of VEGF.

They then tested whether a hexapeptide, which binds TNF and cancels its effect, would block VEGF production and leave blood vessels unaffected. However, their research found that blocking this single pathway was ineffective in preventing the production of VEGF.

"Our findings have shed new light on the potential pathogenesis of this vascular component of rosacea," Dr. Kosmadaki said. "It appears that sun-induced VEGF may play a significant role in rosacea, and its production process seems to involve factors other than TNF. This opens the way for further research that may lead to substantial improvements in treatment or prevention."

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